Resting State Functional Magnetic Resonance Imaging-Tryptophan Hydroxylase-2 Methylation Interaction In Major Depressive Disorder

Aims:Major depressive disorder(MDD)is a common and prevalent mental disorder all over the World.However,about one-third of patients with MDD do not achieve adequate response or remission after antidepressant treatments and become treatment-resistant depression(TRD).Numerous studies have confirmed that the contents of 5-hydroxytryptamine(5-HT)is an important factor affecting MDD and antidepressant response.5-HT biosynthesis is regulated by the rate-limiting enzyme tryptophan hydroxylase-2(TPH2).TPH2 methylation is correlated with MDD and antidepressant effects.Resting-state functional magnetic resonance imaging(rs-fMRI)is applied for detecting abnormal brain functional activity in patients with MDD.We will investigate the interaction between rs-fMRI and TPH2 methylation and in the occurrence of MDD and the efffect of antidepressants.Methods:A total of 300 patients with MDD and 100 healthy controls(HCs)were enrolled,of which 101 patients with MDD and 64 HCs were subjected to MRI at baseline.Blood samples were collected from the participants at baseline.Patients with MDD were evaluated for depressive symptom severity by 17-item Hamilton Depression Rating Scale(HAMD-17)at baseline and at the end of the 2 weeks of antidepressant treatments.The primary clinical outcome measures were treatment response,which was defined as a reduction of≥50%in the HAMD-17 scores from baseline to 2 weeks.The RESTPlus software in MATLAB(2014a)was used to analyze the rs-fMRI data.The amplitude of low-frequency fluctuation(ALFF),regional homogeneity(ReHo)and fractional ALFF(fALFF)were used to identify the changes in the brain networks that were centered in the regions showing abnormal local spontaneous activity.Based on the ALFF,fALFF,and ReHo results in groups,we performed seed-based functional connectivity(FC).The above results were used as regions of interest(ROIs)to extract the average value of brain ROIs regions in the RESTPlus software.T test was used to examine difference the 101 patients with MDD vs 64 HCs in demographic characteristics and abnormal activity of brain area.Generalized linear model analysis was performed to analyze the association between abnormal activity found in rs-fMRI and the effect of TPH2 methylation on the occurrence of MDD and the antidepressants response.R programming language was used to perform the false discovery rate(FDR)test with a statistical significance of p<0.05.Results:291 patients with MDD and 100 HCs were included in the methylation statistical analysis(9 patients with MDD were excluded for various causes in the study).A total of 98 patients with MDD and 61 HCs were included in the further rs-fMRI analysis(3 patients with MDD and 1 HC were excluded due to excessive head movement).According to the reduction ratio of HAMD-17,98 patients with MDD were divided into two groups:53 patients who responded to antidepressant treatments(responders)and 45 patients who failed to respond to the antidepressant treatments(non-responders).Rs-fMRI results showed that the ALFF of right cingulate gyrus,right superior temporal gyrus(STG)and left lingual gyrus were significantly different between patients with MDD and HCs(p<0.05).Rs-fMRI results showed that the ReHo of right middle temporal gyrus(MTG),left STG,left cuneus and left middle occipital gyrus(MOG)were significantly different between patients with MDD and HCs(p<0.05).The significant difference in FC of left anterior cingulate gyrus and right cingulate gyrus,right MTG and right inferior temporal gyrus(ITG),right STG and left STG,right STG and right superior frontal gyrus(SFG),right STG and left inferior occipital gyrus(IOG)and right MTG and right middle occipital gyrus(MOG)were found between the patients with MDD and HCs(p<0.05).The study further found that TPH2-5-203 methylation interacted with ALFF of right STG,TPH2-9-178 methylation interacted with ALFF of left lingual gyrus,TPH2-5-203 methylation interacted with ReHo of right MTG and TPH2-9-178 methylation interacted with FC of right STG and left IOG were associated with the MDD(p=0.004,p=0.048,p=0.018,p=0.021).Rs-fMRI results showed that the brain activities were no different between responders and non-responders.Conclusion:Our study demonstrated that compared with HCs,the functional activities of MDD were abnormal in SFG,temporal lobe,MOG,IOG,lingual gyrus and cuneus.The differences in functional activities of right STG,MTG,left lingual gyrus and IOG between the MDD and the HCs and its association with TPH2 methylation affect the occurrence of MDD.The results suggest that the combination of rs-fMRI and DNA methylation may help to detect MDD as early as possible and perform early intervention and treatment.